Jeff Ross, MD at Foundation Medicine discusses an ASCO 2020 abstract entitled Clinically aggressive malignancies associated with STK11 germline mutations (STK11GCa): A comprehensive genomic profiling (CGP) study
Context:
Peutz-Jehger ‘s Syndrome and a number with malignancies with variable clinical aggressiveness are associated with germline mutations in the STK11 (LKB1) mTOR pathway gene. Recent evidence also ties inactivation of STK11 to failure to benefit from therapy with anti-cancer immune control point inhibitor (IO) in NSCLC.
Approaches:
We detected 103 (0.05 percent) STK11GCa inactivating base substitutions or indels using hybrid capture based CGP based on extracted tumor DNA and a reported “somatic-germline-zygosity” SGZ data analysis algorithm on 212,470 samples of clinically advanced malignancies. On up to 1.1 Mbp of sequenced DNA, tumor mutational burden (TMB) was determined, and 114 loci were determined for microsatellite instability (MSI). IHC (Dako 22C3) determined the phrase PD-L1.
Reviews:
NSCLC was 57 (55 percent) STK11GCa cases, CRC, breast, pancreatic and unknown primary carcinomas were 7 (7 percent) STK11GCa cases each, and gynecologic cancers were 3 (3 percent). STK11 germline alterations were observed in 0.15 per cent NSCLC, 0.03 per cent CRC, 0.03 per cent breast, 0.08 per cent pancreas, 0.06 per cent unknown primary carcinoma and 0.03 per cent gynecological cancers among all samples included in this study. Melanoma, gastroesophageal, HNSCC, intestine, HCC, lymphoma and mesothelioma were additional malignancies harboring STK11GCa. Median patient age at sequencing was 61 years in STK11GCa (range 2 to > 89 years); gender distribution was 52% female and 48% male. The STK11GCa cases had a median of 6.5 genomic alterations (GA)/tumor and 10 percent were co-altered by KEAP1, another IO resistance gene. TP53 (50 percent), KRAS (38 percent with 9 percent in theoretically targetable G12C), CDKN2A (32 percent), CDKN2B (22 percent), SMARCA4 (19 percent), MYC (11 percent), and APC (10 percent) have detected currently untargetable GA. Potentially targetable GA, which has also been related to IO efficacy in some studies, included GA in BRAF (10%), EGFR (9%) and PBRM1 (4%). No rearrangements or fusions were found for the targeting genes. No high cases of MSI have been reported. With 23 percent > 10 mut / Mb and 4 percent > 20 mut / Mb, the median TMB was 5 mut / Mb. Of the 20 cases assessed for STK11GCA, 15 percent were large for PD-L1 (> 50 percent for staining tumor cells).
Findings:
STK11GCa contains a wide range of primary tumors with lack of targetable co-occurring GA. Although these tumors have substantial PD-L1 staining and a subset harbor other potential IO-efficacy markers, inactivated STK11 in these tumors may lead to IO resistance and lack of immunotherapy responsiveness.